few of the more toxic cases the curve rose in spite of rest. There was no case in the series whose metabolism was brought to normal by rest alone. After about two weeks a level is reached and rest will not cause a further drop.

An ice bag over the heart seems to slow its rate and quiet its tumultuousness, and its application serves to keep patients more quiet in bed as they refrain from turning and twisting for fear of displacing it.

Water should be given in abundance in order to eliminate toxic products from the system by the way of emunctories. Distilled water, while not as palatable, will be found to be more efficient. This is partly due to its greater solvent qualities, but more largely due to the fact that patients think it has special merit and will drink it in larger quantities.

The diet of these patients is important. The machinery of their system is being driven under forced draft, and they need fuel to save the consumption of their own tissues. Food should be given every three hours and in as large quantities as possible without creating digestive disturbances.

The administration of various drugs with a view of lessening metabolism has been advocated. Of these, hydrobromate of quinine with ergotine, glycocholate of soda and pancreatic extract have the greatest number of advocates. Means and Aub have tested the action of hydrobromate of quinine on a group of patients and find that it had no apparent effect on the metabolic rate of the cases. While it is only of historic interest, it may be mentioned that the effect of Beebe's serum on metabolism was also tested and found negative. The administration of digitalis is recommended by Willius, not for its effect on metabolism, but because of its influence on the heart.

The use of x-ray has long been advocated in these cases and more recently the application of radium has been recommended, the theory being that a sclerosis is produced which lessens glandular activity. The relative merits of x-ray and radium have not been determined, but it seems that the choice is largely a question of the experience of the operator and the convenience of the patient. Means and Aub tested the effect of the x-ray on a group of cases. These patients had an average metabolic rate of plus 63 per cent. After one or two treatments at intervals of one month there was a reduction to plus 52 per cent. After four or five treatments there was a reduction to plus 40 per cent, and after two or three years' treatment there was a reduction to plus 13 per cent. The advantages claimed for the x-ray method of treatment are that it avoids an operation and is attended by less danger to life. The disadvantages are the increased length of invalidism, the greater difficulty of operating if surgery is ultimately necessary, the possibility of shrinkage of tissues of the neck, the danger of myxedema and of x-ray burns and the liability of treating colloid and cystic goitres which are not benefited.

The injection of boiling water or a solution of quinine and urea into the body of the thyroid has been advised. The theory on which this practice is based is that the destruction of the glandular cells and the obstruction of blood vessels will cut down the output of thyroid secretion. The method is not without immediate or remote disadvantages and dangers. Some patients are so sick that even this apparently simple procedure will cause an acute and perhaps fatal hyperthyroidism, others will not be benefited and a subsequent surgical operation will be made difficult by the adhesions it has caused, and finally the irritation may result eventually in the development of cancer. Balfour reports one hundred and three cases of malignant disease of the thyroid and it is a significant fact that seven gave history of having been treated by the injection method.

If a patient has time and money and is willing to make a pet of a diseased gland and try to humor it back to a normal condition, then palliative measures may be tried, but it is generally conceded at the present time that the safest, surest and quickest way to effect a cure is by surgery. The practice of destroying a portion of a gland in order to lessen its physiological activity is certainly illogical, but it is the best we can do until some chemical antidote for thyroxin is discovered.

The operations done for hyperthyroidism are ligations and partial thyroidectomies. The advocates of ligation state that while the benefits which follow the operation are marked, they are not permanent and that they should only be employed either as a test of a patient's reaction to trauma in cases where there is a doubt of the individual's ability to stand a thyroidectomy, or as a means to get a patient in condition for a more radical operation when it is obvious that at the time a thyroidectomy could not be done without great hazard. Observations in the various surgical clinics of the country show that the number of ligations being done is steadily diminishing and personally I have given them up altogether. The favorable results attributed to ligations cannot be explained on an anatomical or physiological basis. The theory that ligations act by cutting down the blood supply is refuted by the experience of every operator who knows that tying one or more of the principal arteries does not materially diminish the vascularity of the gland. It is stated that all the blood in the body passes through the thyroid once every hour and ligations actually increase the blood supply by the formation of collateral branches. The theory that ligations interfere with trophic influence is an explanation that has no physiologic parallel in other parts of the body and is an argument about as mysterious and no more logical than those advanced to support Christian Science. The effects of ligations are in my opinion largely due to psychic influences and to the subsequent treatment of the patient, and the same results can be secured by safer and less

heroic means. In mild cases ligations are unnecessary, and in severe cases they are more dangerous than a lobectomy or partial thyroidectomy. The greatest danger of an operation for exophthalmic goitre is acute postoperative hyperthyroidism and this is caused not by the amount of the gland taken out but by the amount of the gland left in, and can be best minimized by the removal of a large portion of the thyroid. In the early days of my work I had some bad results because I was timid and did not remove enough of the gland. With increasing confidence I have taken out more and more tissue and have secured better immediate results and have seen no remote bad consequences. I now do a double partial lobectomy, only leaving a small portion of the gland attached to the posterior capsule on either side. This leaves sufficient thyroid tissue to carry on the normal functions of the body, protects the recurrent laryngeal nerve and other important structures from injury, and gives good cosmetic results, as it does not destroy the symmetry of the neck.

The results of partial thyroidectomy are prompt and permanent. If the operation does not effect a satisfactory cure, it is because either not enough of the gland has been removed or that the operation has been delayed until the patient's symptoms are no longer due to hyperthyroidism, but to organic changes in the vital organs as well.

I do not wish it to be inferred that a radical operation should be done for a bad toxic or exophthalmic goitre without careful preliminary study and often prolonged treatment of each individual case. The patient should be put to bed, given absolute physical and mental rest, an ice bag applied to the chest, and water and food properly regulated. The fluctuations of the disease should be carefully watched and the operation fixed for the most propitious time. Every effort should be made to inspire the patient with confidence and to relieve apprehension and fears.

A few patients will not bear transportation and should be operated on in their room without moving them from bed. Some do best under local anesthesia, others require light nitrous oxide oxygen in addition. Often after the removal of the desired amount of glandular tissue it is wise to pack the wound and delay closure for two or three days. It is always well to provide for liberal drainage. After the operation water should be given by rectum or subcutaneously, morphia without atropia administered to relieve pain and quiet restlessness, and cold sponges or ice packs employed to combat fever if elevation of temperature occurs.

TRIMBLE LECTURE

EXPERIMENTAL MODIFICATION OF BONE AND TOOTH DEVELOPMENT

BY E. V. McCOLLUM, M.D.

School of Hygiene, Baltimore

It is desirable, in order to present the discussion of bone and tooth development in its proper setting, to mention some of the principal points which have been established regarding what constitutes a satisfactory diet. Twenty years ago it was generally accepted that a diet which contained an approved amount of protein, digestible carbohydrates, fats, and ash substances would prove satisfactory in nutrition. The results of modern experimentation have shown that there are very great differences in the quality of proteins in foods of different kinds. Gelatin and certain other proteins, when fed as the sole source of protein, are incomplete and inadequate, and cannot support either maintenance or growth. The proteins of the bean and the pea, when they form the sole source of nitrogen, are of very poor quality.

We now employ the working hypothesis that an adequate diet must contain not only suitable amounts of protein, but protein of good quality, a source of the sugar glucose, nine inorganic elements (sodium, potassium, calcium, magnesium, chlorine, iodine, phosphorus, sulphur and iron), and four substances, the chemical nature of which we know nothing about and which we designate collectively as vitamins. Three of these are now designated vitamin A, vitamin B and vitamin C. The fourth has not been called vitamin D, since Funk has called a substance which stimulates the growth of yeast vitamin D. The nine inorganic elements must be supplied in appropriate compounds, but all except sulphur can be supplied in the form of inorganic salts. The element, sulphur, must be supplied in organic combination in the form of the amino-acid cystin, which is a digestion product of proteins. We have come to appreciate that the animal organism is much more sensitive to the amounts and proportions of certain of the essential inorganic elements in the diet than was formerly supposed.

Our knowledge of the several vitamins is limited to the effects observed when one or another of them is left out of the diet, it being otherwise appropriately constituted for the promotion of growth and health. The vitamin A is most abundant in certain fats, but the fats of mammalian

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liver, kidney, pancreas, thymus and other glandular structures contain it in abundance. Cod liver oil, butter fat and egg yolk fats are likewise good sources of it, but no vegetable fat has been found to contain demonstrable amounts of this substance. It is, however, present in certain vegetable foods, notably in such leaves as spinach, alfalfa, clover and lettuce, and curiously enough is more abundant in certain pigmented roots such as the carrot and yellow turnip. Yellow corn is far superior to white corn in its content of this vitamin.

Vitamin B is widely distributed and relatively abundant in most of our natural foods. Commercial sugars, starches, fats and oil from both vegetable and animal sources do not contain it. Wheat flour, degerminated cornmeal and polished rice are lacking in this substance. Foods especially rich in the vitamin B are wheat germ, yeast, liver, kidney, and the thin type of plant leaf. Whereas the glandular structures are rich in vitamin B the muscle tissues are practically devoid of it.

The vitamin C is the antiscorbutic principle. It is found in liver and other glandular organs when uncooked, and in all fresh, unheated fruits and vegetables; but is not present to any appreciable extent in cooked, stale or preserved foods.

I shall speak a little later more in detail about the fourth vitamin, which was demonstrated within the past year.

In 1917 the fact was established that a type of ophthalmia which had for years been occasionally observed in poorly-nourished experimental animals was actually a never failing symptom of a deficiency of the vitamin A. Previous to that time it had been looked upon as an infectious eye disease afflicting poorly-nourished animals. Recently Dr. S. Mori, working in my laboratory, made an extensive study of the anatomical changes resulting from a lack of the vitamin A. He removed all the structures within the bony orbit, fixed, cut and stained them, and found that with the development of the symptoms characteristic of the vitamin A deficiency the first observable change is in the lachrymal gland. This ceases to produce tears. With the cessation of the flow of tears the eyeball and conjunctival sac become dry. When the eye is no longer bathed in tears, bacteria grow freely in the conjunctival sac and upon the surface of the eye. Drying results in the cornification of the external coating of the eye and bacterial growth leads to the migration of leucocytes which comes to fill the anterior chamber of the eye. Some of these migrate to the surface of the eye and, disintegrating, form a sticky exudate which tends to paste the eyelids together. Ulceration and perforation are a constant feature of the later stages of vitamin A deficiency.

Doctor Mori also found that the salivary glands pass into a resting condition when the animal is deprived of vitamin A. This results in